Role of adolescent stress in the acceleration of Alzheimer's disease related-cognitive impairment

项目总结/摘要 我们的NIMH R 01项目（R 01 MH 116869）的主要目标是阐明青少年压力对社会的作用。 产后期的认知。我们发现青少年的心理压力， 怀孕/分娩的压力事件，导致产后社会行为的长期缺陷 期我们还证明了压力大坝中的社会行为缺陷是由以下因素引起的： 糖皮质激素受体（GR）介导的前额叶（AI）-前边缘皮质（PrL）功能改变 预测。这些结果显示了增强的GR信号在AI-PrL途径中的因果作用， 青春期压力诱发的产后社会行为缺陷。最近的研究表明， 女性患阿尔茨海默病（AD）的风险明显高于男性。早期生活 压力促使AD的进展并加重症状。AI和背侧前扣带回的病理学 皮质[dACC，与啮齿动物中的PrL同源]与AD有关。然而，机制 电路水平的缺陷的根本原因尚不清楚。通过修改我们正在进行的R 01项目的协议， 我们也许能够探索这个回路的功能障碍和加速之间的关系。 女性AD相关表型。在这项拟议的补充研究中，我们将检验以下假设： 青少年的社会隔离，加上怀孕/分娩的压力事件，加速了发病 通过AI-PrL功能改变的AD相关缺陷的社会行为。为了解决我们的假设，我们将 追求以下两个具体目标：在目标1中，我们将研究青少年的社会孤立是否 加速了5xFAD母鼠中AD相关的社会行为缺陷的发生。血浆皮质酮水平， 将测量Aβ和淀粉样蛋白斑块以及突触密度，以检查青少年压力的影响 对5xFAD母鼠HPA轴和AD相关神经病理学的调节。在目标2中，我们将研究如何 一种新的皮质-皮质通路AI-PrL投射的介导改变了5xFAD母鼠的社会行为 暴露在青少年的社会孤立中这项补充研究将产生关键数据，以了解 青少年心理社会应激对AD患者神经元功能和行为的影响这一发现 还将刺激研究在关键时期操纵特定回路，以干预与AD相关的 病理和症状。

PROJECT SUMMARY/ABSTRACT The primary goal of our NIMH R01 project (R01MH116869) is to elucidate the role of adolescent stress on social cognition in the postpartum period. We have discovered that adolescent psychosocial stress, in conjunction with the stressful events of pregnancy/delivery, leads to long-lasting deficits in social behaviors in the postpartum period. We have also demonstrated that the social behavioral deficits in stressed dams are caused by glucocorticoid receptor (GR)-mediated functional alteration of anterior insula (AI)-prelimbic cortex (PrL) projections. These results show the causal role of enhanced GR signaling in the AI-PrL pathway underlying adolescent stress-induced social behavioral deficits in the postpartum period. Recent studies demonstrate that females have a significantly greater risk for the development of Alzheimer’s disease (AD) than males. Early life stress drives the progression of AD and exacerbates symptoms. Pathology in AI and dorsal anterior cingulate cortex [dACC, homologous to the PrL in rodents] have been implicated in AD. However, the mechanisms underlying the deficits at the circuit level remain unclear. By modifying the protocol of our ongoing R01 project, we may be able to explore the relationship between the dysfunction of this circuit and the acceleration of the AD-related phenotypes in females. In this proposed supplemental study, we will test the hypothesis that adolescent social isolation, in conjunction with the stressful events of pregnancy/delivery, accelerates the onset of AD-related deficits in social behaviors via AI-PrL functional alterations. To address our hypothesis, we will pursue the following specific two Aims: In Aim 1, we will examine whether adolescent social isolation accelerates the onset of AD-related deficits in social behaviors in 5xFAD dams. Plasma corticosterone levels, plaques of Aβ and amyloid, and synaptic density will be measured to examine the effects of adolescent stress on regulation of the HPA axis and AD-related neuropathology in 5xFAD dams. In Aim 2, we will investigate how mediation of the AI-PrL projections, a novel cortico-cortical pathway, alters social behaviors in 5xFAD dams exposed to adolescent social isolation. This supplemental study will generate critical data to understand the influence of adolescent psychosocial stress on neuronal function and behavior in the context of AD. The finding will also stimulate research to manipulate a specific circuit at a critical period in order to intervene in AD-related pathology and symptoms.